Evolving a bigger brain with human DNA

The human version of a DNA sequence called HARE5 turns on a gene important for brain development (gene activity is stained blue), and causes a mouse embryo to grow a 12 percent larger brain by the end of pregnancy than an embryo injected with the chimpanzee version of HARE5. Credit: Silver lab, Duke University

The size of the human brain expanded dramatically during the course of evolution, imparting us with unique capabilities to use abstract language and do complex math. But how did the human brain get larger than that of our closest living relative, the chimpanzee, if almost all of our genes are the same?

Duke scientists have shown that it's possible to pick out key changes in the genetic code between chimpanzees and humans and then visualize their respective contributions to early brain development by using mouse embryos.

The team found that humans are equipped with tiny differences in a particular regulator of gene activity, dubbed HARE5, that when introduced into a mouse embryo, led to a 12% bigger brain than in the embryos treated with the HARE5 sequence from chimpanzees.

The findings, appearing online Feb. 19, 2015, in Current Biology, may lend insight into not only what makes the human brain special but also why people get some diseases, such as autism and Alzheimer's disease, whereas chimpanzees don't.

"I think we've just scratched the surface, in terms of what we can gain from this sort of study," said Debra Silver, an assistant professor of molecular genetics and microbiology in the Duke University Medical School. "There are some other really compelling candidates that we found that may also lead us to a better understanding of the uniqueness of the human brain."

Every genome contains many thousands of short bits of DNA called 'enhancers,' whose role is to control the activity of genes. Some of these are unique to humans. Some are active in specific tissues. But none of the human-specific enhancers previously had been shown to influence brain anatomy directly.

In the new study, researchers mined databases of genomic data from humans and chimpanzees, to find enhancers expressed primarily in the brain tissue and early in development. They prioritized enhancers that differed markedly between the two species.

The group's initial screen turned up 106 candidates, six of them near genes that are believed to be involved in brain development. The group named these 'human-accelerated regulatory enhancers,' HARE1 through HARE6.

The strongest candidate was HARE5 for its chromosomal location near a gene called Frizzled 8, which is part of a well-known molecular pathway implicated in brain development and disease. The group decided to focus on HARE5 and then showed that it was likely to be an enhancer for Frizzled8 because the two DNA sequences made physical contact in brain tissue.

The human HARE5 and the chimpanzee HARE5 sequences differ by only 16 letters in their genetic code. Yet, in mouse embryos the researchers found that the human enhancer was active earlier in development and more active in general than the chimpanzee enhancer.

"What's really exciting about this was that the activity differences were detected at a critical time in brain development: when neural progenitor cells are proliferating and expanding in number, just prior to producing neurons," Silver said.

The researchers found that in the mouse embryos equipped with Frizzled8 under control of human HARE5, progenitor cells destined to become neurons proliferated faster compared with the chimp HARE5 mice, ultimately leading to more neurons.

As the mouse embryos neared the end of gestation, their brain size differences became noticeable to the naked eye. Graduate student Lomax Boyd started dissecting the brains and looking at them under a microscope.

"After he started taking pictures, we took a ruler to the monitor. Although we were blind to what the genotype was, we started noticing a trend," Silver said.

All told, human HARE5 mice had brains 12% larger in area compared with chimpanzee HARE5 mice. The neocortex, involved in higher-level function such as language and reasoning, was the region of the brain affected.

Producing a short list of strong candidates was in itself a feat, accomplished by applying the right filters to analysis of human and chimpanzee genomes, said co-author Gregory Wray, professor of biology and director of the Duke Center for Genomic and Computational Biology.

"Many others have tried this and failed," Wray said. "We've known other people who have looked at genes involved in brain size evolution, tested them out and done the same kinds of experiments we've done and come up dry."

The Duke team plans to study the human HARE5 and chimp HARE5 mice into adulthood, for possible differences in brain structure and behavior. The group also hopes to explore the role of the other HARE sequences in brain development.

"What we found is a piece of the genetic basis for why we have a bigger brain," Wray said. "It really shows in sharp relief just how complicated those changes must have been. This is probably only one piece—a little piece."

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12 comments

The human brain grew in the context of tribalism and competition among equals. Tribes whose members were able to follow and execute increasingly complex strategies against enemy tribes, and who were capable of conceptualizing, coordinating, communicating, and memorizing them as a group would tend to be victorious.

Groups which could develop and improve upon weapons technologies more effectively than their enemies, and employ this tech in conjunction with complimentary battlefield strategy, would also enjoy a distinct advantage.

Victors consistently killed the males and incorporated the females, thereby accelerating the development of the intellect far beyond what would be expected of natural selection.

Alfie, Our records are not only a "few fossils", there is also the entire field of archeology.Otto is correct because no matter how you look at it, warfare has undoubtedly influenced our evolution. I mean most technologies are born out of war, I'm sure one of the first things we did with a rock was hit someone in the head with it.

But war is embedded in our psychology. Bonobos are friendly, but common chimpanzees engage in war between tribes, literally pillaging them. Chimps also have complex strategies in hunting which probably also helped us evolve the way we did. Gorillas, chimps, and humans will kill the men of other communities and start having sex with the girls. Chimps and gorillas also explicitly kill children in conquered tribes that they didn't father, and in extreme cases people do that too, like in Cambodia.It's why we're racist and xenophobic, it's for our defense and in our genetic interest. Unfortunately society evolves faster than our habits

...warfare has undoubtedly influenced our evolution. I mean most technologies are born out of war...

"Warfare" is just another form of the competition for resources that is an inherent element in all species. Composition is the primary driver for selection, and is influenced by the ability of the individual to gain advantage over other members in the population. Increasing our individual fitness serves to increase the amount of our DNA in the population, thus forming the basis for the formation of tribes with related individuals, and the subsequent willingness to commit harm to those which are acting to oppose the continuance of our DNA in the population. DNA is selfish, and at the end of the day, we're still just animals (albeit animals with a superiority complex and the capability for massive amounts of violence).

On the article, I'm fascinated by the selective pressures which led to selection for increased brain size. We can reasonably presume that the mutations which led to the divergence of Tribe Hominini are still possible in the other Family Hominidae members, and have likely occurred across the last few million years. Alas, these mutations did not give them an advantage in their environments, or at least enough of an advantage to be selected-for.

The brain is biologically expensive to form and maintain, and as much a critical vulnerability as it is a potential enabler. Under nutritional selective pressures, if something is not contributing to one's fitness, it is often selected against. One must wonder what the conditions were where the strength, size, hide, and teeth of the great apes was somehow a liability to fitness, where as brain development which had been there-to historically unnecessary was so beneficial to be a driver of selection.

One must wonder what the conditions were where the strength, size, hide, and teeth of the great apes was somehow a liability to fitness, where as brain development which had been there-to historically unnecessary was so beneficial to be a driver of selection

Because brains always tend to prevail over brawn on the battlefield. Read Sun Tsu; 'all of war is deception'. Read david and goliath.

The human brain is indeed energy-hungry, damage and defect-prone, and begins to degrade soon after adolescence. This may be why humanity seems to degrade with each generation without the constant group selection process of conflict, which is what gave us these unwieldy thinking machines in the first place. Wheat from chaff as the bible calls it. Augustine of hippo equated it with refining gold or something.